Process for the conversion of 5alpha,6alpha-epoxy steroids to the corresponding 6beta-fluoro-5alpha-hydroxy steroids



United States Patent ice PROCESS FOR THE CONVERSION OF Seams-EPOXY STEROIDS TO THE CORRESPONDING 6,8-FLU- ORO-Sa-HYDROXY STEROIDS Hugh V. Anderson, Oshtemo Township, Kalamazoo County, and Ingemar B. Forsblad, Portage Township, Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed Jan. 9, 1963, Ser. No. 250,244

Claims. (Cl. 260-3971) This invention relates to an improved process for preparing 6-fluoro steroids. More particularly it relates to an improved process for the conversion of 5a,6a-epoxy steroids to the corresponding 6fi-fluoro-5a-hydroxy steroid by means of hydrogen fluoride in the presence of water and a metal fluoride salt.

Saturated and unsaturated 5a,6a-epoxy steroids of the pregnane and androstane series can be hydrohalogenated in accordance with the improved process of this invention. Representative 5a,6a-epoxy steroid starting materials, the process and the products obtained are illustratively shown by the following partial structural formulae:

RI RI W F X I 151 0' our in which R is an alkylene radical containing not more than 8 carbon atoms, inclusive, and the attaching oxygen to carbon bonds are separated by a chain of at least 2 and not more than 3 carbon atoms, e.g., ethylene, 1,2- propylene, 1,3-propylene, 2,2-dimethyl, 1,3-propylene, 2,3 butylene, 2,4 amylene, 4 methyl 1,2 amylene, 6 methyl 1,4 hexylene, 1,2 heptylene, 3,4 heptylene, 1,3-octylene, etc. and X is selected from the group consisting of the fi-hydroxymethylene radical; the esterified B-hydroxymethylene radical which is defined as above and the carbonyl radical.

The following are typical of the conversions represented by the above formulae:

Alkyl 3,11 diketo 5a,6a-epoxy 17(20) [cis] pregnen-21-oate 3-alkylene ketal to the corresponding alkyl 3,11 dike-to 5a hydroxy 6,8 fluoro 17(20)- [cis]-pregnen-Zl-oate;

50,6a epoxy 17B hydroxyandrostane 3 one 3- ethylene ketal to 5a,17B dihydroxy 6B fluoroandrostan-3-one;

50,6a epoxy 17B hydroxy 19 norandrostane 3,11- dione 3 ethylene ketal to 5a,17,8 dihydroxy 6,8- fluoro-19-norandrostane-3 ,1 l-dione;

3,261,850 Patented July 19, 1966 5a,6a epoxy 170a hydroxypregnane 3,20 dione 17- acetate 3 propylene ketal to 5a,17a dihydroxy 6B- fiuoropregnane-3,20-dione l7-acetate;

5a,6a epoxy 11/3 hydroxypregnane 3,20 dione 3,

20 bis (ethylene ketal) to 504,115 dihydroxy 6/3- fluoropregnane-3,20-dione;

Methyl 2a methyl 3,11 diketo 50,6a epoxy- 17(20) [cis] pregnen 21 oate 3 ethylene ketal to methyl 20c methyl 3,11 diketo 5a hydroxy- 6fl-fluoro- 17 20 [cis -pregnene-2 l-oate;

5a,6a epoxy c fluoro 115,175 dihydroxy 17amethyl androstane 3 one 3 ethylene ketal to 6,8,9a diffuoro 17a methyl 5a,11fl,17fi trihydroxy-androstan-3-one;

5a,6u epoxy 21 hydroxy pregnane 3,11,20 trione 3,20 bis (ethylene ketal) to 50,21 dihydroxy 6B- fluoropregnane-3 ,1 1,20-trione;

5a,6a epoxy 1113,17a,21 trihydroxypregnane 3,20- dione 21 acetate 3,20 bis(ethylene ketal) to 6,8- fluoro 5uc,11,B,l7oc,2l tetrahydroxypregnane 3,20- dione 21-acetate;

3,8 hydroxy 505,60: epoxypregnan 20 one to 35,511-

dihydroxy-6/3-fluoropregnan-20-one, and

50,6a epoxy 35,1711 dihydroxypregnan 20 one 3- acetate to 3fi,5o,17a trihydroxy 6B fluoropregnan- 20-one 3-acetate.

The 5a-hydroxy-6B-fluorosteroids produced by the improved process of this invention are useful intermediates in the production of known, highly active, A and A -6afluoro-steroid compounds, e.g., US. Patents 2,838,492; 2,838,497 and 2,838,540.

Heretofore 50,6oc-6POXY-Si61'OiClS have been converted to the corresponding 5a-hydroxy-6/3-fluoro steroid in only relatively low yields, 50% and less, by the use of anhydrous hydrogen fluoride in an organic solvent such as tetrahydrofuran and dimethylformamide, e.g., US. Patents 3,049,566 and 3,007,923, respectively, or by the use of aqueous hydrogen fluoride in the presence of an organic solvent, such as methylene chloride, e.g., US. Patent 2,838,497.

According to the improved process of this invention, it has now been discovered that 5u,6a-epoxy steroids can be converted to the corresponding 5a-hydroxy-6B-fluoro steroid in greatly increased yields, and in improved quality of product. The unexpected and exceptionally high yields obtained by the process of this invention greatly overcomes any inherent disadvantage which might be construed to exist because of the relatively low reaction temperatures necessary in carrying out the reaction. The improved process of this invention possesses the additional advantage of yielding final products which are readily recovered from the reaction medium by conventional methods in relatively pure form.

In carrying out the improved process of this invention the selected Saba-epoxy steroid is preferably added to a reaction medium of hydrogen fluoride, Water and a metal fluoride salt, e.g., sodium fluoride, potassium fluoride, lithium fluoride, sodium bifluoride, potassium bifluoride, silver fluoride, calcium fluoride, and the like; alkali metal fluorides are preferred and sodium fluoride and potassium fluoride are especially advantageous. This reaction medium is conveniently prepared by adding the fluoride salt and water to cold hydrogen fluoride, at a temperature below about 10 C. to avoid excessive loss of hydrogen fluoride. The selected 5a,6a-epoxy steroid is then added to this reaction medium either as a solid, preferably in a finely divided form or more advantageously in solution in a minimum amount of a suitable organic solvent in which the steroid is readily soluble, e.g., methylene chloride, chloroform, ethylene chloride, carbon tetrachloride, etc., the smallest amount of solvent possible is desirable in order to prevent the formation of a two-phase system in the reaction medium.

In the improved process of this invention the hydrogen fluoride serves both as a solvent for the steroid and as a reagent. The reaction is catalyzed by the presence of water and the fluoride salt. The reaction is conducted using an excess of hydrogen fluoride to steroid reactant. The molar concentration of hydrogen fluoride relative to starting 5a,6 x-epoxy steroid can range from a mole ratio of about 25:1 to 500:1, a range of about 60:1 to 300:1 is generally preferred and a range of about 150:1 to 160:1 is especially advantageous. The molar ratio of flouride salt to hydrogen fluoride present in the reaction medium can range from a mole ratio of about 1:10 to 1:625, however, about 1:10 to 1:50 is generally preferred and a range of about 1:15 to 1:25 is especially advantageous. The mole ratio of water present in the reaction medium can range from a molar concentration of water relative to hydrogen fluoride of from about 1:5 to 1:500, a range of about 1:10 to 1:300 is preferred, and a range of about 1:20 to 1:30 is especially advantageous. The improved process of this invention is operative using higher ratios of hydrogen fluoride to steroid and fluoride salt to hydrogen fluoride but larger amounts only add to the cost of the process without producing substantial improvements over the prescribed ratios.

The reaction is preferably carried out under conditions of continual stirring or other agitation. The reaction which is exothermic is carried out below about 50 C., a temperature range of 50 C. to 80 C. is preferred, and with about 50 C. to 65 C. being particularly advantageous. The steroid can be added continuously or portionwise to the reaction medium at such a rate that the prescribed temperatures can be maintained. After the steroid has been added it is desirable to continue agitation of the reaction mixture within the prescribed temperature range until the reaction is essentially complete.

After completion of the fluorination reaction, the desired product is easily recovered from the reaction medium by conventional methods, e.g., the reaction mixture can be quenched in aqueous alkali, preferably below C. to avoid the formation of undesirable by-products. Any alkali can be used for this purpose, although aqueous alkali metal carbonates such as potassium or sodium carbonate, are preferred. The amount of alkali should be sufficient to neutralize the excess hydrogen fluoride and render the mixture slightly alkaline. The 6;? fluoro 5a hydroxy steroid precipitates from this aqueous mixture as a crystalline solid which is readily recovered by filtration. The 6,8-fluoro-5a-hydroxy steroid thus obtained can be further purified by recrystallization from a suitable organic solvent in accordance with methods well known in the art.

The following examples illustrate the application of the above-described process but are not to be construed as limiting.

17(20) -[cis]-pregnen-21-0ate A mixture of 22.7 g. of sodium fluoride, 6.70 g. of water and 200 g. of anhydrous hydrogen fluoride was cooled to about 65" C.; 27.0 g. of methyl 3,11-diketo-5a,6aepoxy-17(20)-[cis]-pregnen-21-oate 3-ethylene ketal was then added slowly as a solid with agitation keeping the temperature below 60 C. by external cooling. After all of the steroid starting material was added the reactionmixture was stirred for an additional 20 minutes keeping the temperature between 65" C. and 70 C. The reaction mixture was then quenched into a solution of 1,240 g. of potassium carbonate in 6.5 liters of icewater about 1:1. The mixture was stirred for about /2 hour keeping the temperature below 10 C. The precipitate thus obtained was collected on a filter, washed with about 2 liters of cold water and dried in a vacuum oven at 70 C. to give 25.0 g. (98.4% yield) of methyl 3,11 diketo 5oz hydroxy 6e fluoro 17(20)-[cis]- pregnen-Zl-oate, M.P. 242.0 C., dec.; [ab +21 (dioxane); 12% impurities by papergram.

Analysis.-Calcd. for C H O F: F, 4.84 Found: F, 4.60.

Recrystallization from methanol gave methyl 3,11- diketo 50c hydroxy 6/3 fluoro 17,20[cis]-pregnen- 21-oate, M.P. 232.5 C., dec.; [a] +23 (dioxane).

Example 2.Methyl 3,11diket0-5a-hydr0xy-6 8-flu0r0- 17(20) [cis]-pregnen-21-oate A cold reactor was charged with 7.4 parts (the parts referred to in this example are by weight) of hydrogen fluoride and cooled to below 50 C. with agitation, 0.84 part of sodium fluoride was then added keeping the temperature below 30 C. The hydrogen fluoride mixture was then again cooled to below 50 C. and 0.248 part of water was added slowly again keeping the temperature below 30 C. This hydrogen fluoride mixture was then cooled to below '60 C. and 1.0 part of methyl 3,11diketo-5a,6a-epoxy-17('20)- [cis]-pregnen-21-oate 3-ethylene ketal dissolved in 1.67 parts of methylene chloride was added slowly at such a rate that the temperature was maintained below 50 C. Approximately 0.33 part of additional methylene chloride was used to rinse all of the steroid solution into the reaction vessel. The reaction mixture was then stirred for approximately 2 hours keeping the temperature between 50' C. and 65 C. At the end of the reaction period the reaction mixture was slowly added to a solution of 45.9 parts of potassium carbonate in parts of water containing 50 parts of ice. The temperature was maintained below 10 C. during the addition. The reactor was rinsed with 0.8 part of acetone which was added to the neutralizing solution and the neutralized mixture was then stirred for /2 hour. The crystalline product thus obtained was collected on a filter and washed thoroughly with cold water. The product was then dried at 70-75 C. in vacuum oven to give 0.92 part (97.7% yield) of methyl 3,11-Clik6iO-5u-hY- droxy-65-fluoro-17(20)-[cis]pregnen-Zl-oate, M.P. 220 240 C., [a] +22 (dioxane).

The product thus obtained can be further purified if desired by recrystallization from a suitable organic solvent, e.g., methanol.

The procedure of Example 2 was repeated using a stoichiometric equivalent amount of potassium fluoride in place of sodium fluoride to give a substantially equivalent yield of methyl 3,1l-diketo-5a4hydroxy-6fi fluoro- 17(20)-[cis]-pregnene21-oa/te.

In the same manner other metal fluoride salts, e.g., those previously listed, can be substituted for sodium or potassium fluoride to give substantially the same results.

We claim:

1. In a process for converting a steroid, selected from the group consisting of saturated and unsaturated 511,604- epoxy steroids of the pregnane and androstane series to the corresponding 6,8fluoro-5a-hydroxy steroid by reacting the said Sc m-epoxy steroid with hydrogen fluoride the improvement which comprises carrying out the reaction in the presence of water and a metal fluoride salt at temperatures below about 50 C.

2. In a process for converting a steroid, selected from the group consisting of saturated and unsaturated 5a,6aepoxy steroids of the pregn-ane and androstane series to the corresponding 6;6-fluoro-5a-hydroxy steroid by reacting the said 5a,6a-ep'oxy steroid with hydrogen fluoride the improvement which comprises carrying out the reaction in the presence of 'water and an alkali metal fluoride salt at a temperature within the range of from about '50 C. to C. wherein .the mole ratio of hydrogen fluoride to the selected 5a,6u-epoxy steroid is within the range of from about 60:1 to 300:1, the

mole ratio of water to hydrogen fluoride is Within the range of from about 1:10 to 1:300 and the mole ratio of alkali metal fluoride salt to hydrogen fluoride is Within the range of from about 1:10 to 1:50.

'3. The process of claim 2 for the production of methyl 3,11 diketo-Sa-hydroXy-6flfluor-17( 20)-[cis]-pregnen- 21-oate, wherein the starting steroid is methyl 3,11-diketoa,6o epoxy 17 [cis]-pregnen-Zl-oate 3-et-hylene ketal.

4. The process which comprises reacting methyl 3,1-1- diketo-5a,6a-epoXy-l7 (20 [cis] -pregnen2 l-oate 3-ethylene ketal with hydrogen fluoride in the presence of Water and sodium fluoride at temperatures Within the range of from about to C. wherein the mole ratio of hydrogen fluoride to the starting 5a,6a-epoxy steroid is Within the range of from about :1 to :1, the mole ratio of water to hydrogen fluoride is within the range of from about 1:20 to 1:30 and the mole ratio of 6 sodium fluoride to hydrogen fluoride is within the range of from about 1:15 to 1:25, to produce methyl 3,11- diketo 65 fluoro-5a-hydroXy-17(20)-[cis]-pregnen 21- oate.

5. The process of claim 4 wherein the alkali metal salt is potassium fluoride.

References Cited by the Examiner UNITED STATES PATENTS 2,838,502 6/1958 Beal et al 260-23955 3,009,930 11/1961 Reimann et al 260-3973 3,022,295 2/1962 Berg et al. 260-23955 3,086,032 4/ 1963 Gerber 260-397.3

LEWIS GOTTS, Primary Examiner.

ELBERT L. ROBERTS, Assistant Examiner. 

4. THE PROCESS WHICH COMPRISES REACTING METHYL 3,11DIKETO-5A,6A-EPOXY-17(20)-(CIS)-PREGNEN-21-OATE 3ETHYLENE KETAL WITH HYDROGEN FLUORIDE IN THE PRESENCE OF WATER AND SODIUM FLORIDE AT TEMPERATURE WITHIN THE RANGE OF FROM ABOUT -50* TO -65*C. WHEREIN THE MOLE RATIO OF HYDROGEN FLUORIDE TO THE STARTING 5A,6A-EPOXY STEROID IS WITHIN THE RANGE OF FROM ABOUT 150:1 TO 160:1, THE MOLE RATIO OF WATER TO HYDROGEN FLUORIDE IS WITHIN THE RANGE OF FROM ABOUT 1:10 TO 1:30 AND THE MOLE RATIO OF SODIUM FLUORIDE TO HYDROGEN FLUORIDE IS WITHIN THE RANGE OF FROM ABOUT 1:15 TO 1:25, TO PRODUCE METHYL 3,11DIKETO - 6B - FLUORO-5A-HYDROXY-17(20)-(CIS)-PREGNEN 21OATE. 